Despite the considerable differences between human (hESCs) and mouse (mESCs) ESCs in terms of the signalling requirements for their culture and propagation, studies using kinase inhibitors and genetic approaches have shown that both types of ESCs require active PI3K/AKT signalling to maintain their undifferentiated properties. Treatment of mESCs with either a general PI3K or p110β-specific inhibitor compromises their pluripotency, and deficiency of PI3K genes also results in loss of pluripotency in mESCs (
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;
Kingham and Welham, 2009
). Similarly, PI3K inhibition in hESCs results in the downregulation of pluripotency markers concomitant with the upregulation of lineage-specific genes, which together strongly suggest the loss of pluripotency (
Armstrong et al., 2006
;
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;
Singh et al., 2012
). Given that active cell proliferation is essential for ESC self-renewal and that PI3K plays a key role in regulation of cell proliferation, this implicit requirement for PI3K in ESC self-renewal is probably expected. In fact, knockout of
Pten
in both mESCs and hESCs duly augments the proliferation and survival of these cells (
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). However, PI3K deficiency appears to have no obvious effect on ESC survival or proliferation (
Paling et al., 2004
), suggesting that PI3K signalling is not limited to driving the growth and survival of ESCs, but also in inherently preserving their pluripotent properties.

Interestingly, despite the fact that PI3K signalling is active in both mESCs and hESCs, it is unclear whether this activation is through canonical induction via IGF1/insulin or whether it is simply a resultant effect from the activation of other pathways (
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). PI3K signalling in mESCs was found to be activated by an ESC-specific RAS protein (ERAS) via direct interaction with its p110 subunit (
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). However, deficiency of ERAS does not affect pluripotency of mESCs, indicating that the PI3K-medicated effect on pluripotency is not associated with ERAS. By utilising chemically defined culture conditions, it was proposed that leukaemia inhibitory factor (LIF), a key player in maintenance of mESC self-renewal, may activate PI3K signalling through phosphorylation of its receptor JAK (
Niwa et al., 2009
;
Paling et al., 2004
), yet it remains unclear how LIF induces both JAK-STAT3 and JAK-PI3K pathways. Similarly, activation of PI3K in hESCs may also occur through non-canonical means. The presence of basic fibroblast growth factor (bFGF) in hESC cultures is thought to stimulate PI3K signalling in both fibroblast-conditioned medium or chemically defined culture conditions by activating EGFR and IGF1R (
Zoumaro-Djayoon et al., 2011
) Given that heregulin (neuregulin 1) and IGF1 can act in the absence of FGF to maintain hESC pluripotency, FGF-mediated PI3K induction appears to be the more crucial effect in preserving hESC properties opposed to stimulation of the FGF/RAS/MAPK axis (
Singh et al., 2012
). However, an important caveat to such a conclusion is that both heregulin and IGF1 can also conversely activate RAS/MAPK signalling, making it difficult to distinguish the independent effects of either pathway on pluripotency. Nonetheless, a recent report showed that under similar defined culture conditions, insulin but not bFGF, is able to activate PI3K signalling (
Ho et al., 2015
), suggesting that the magnitude of FGF-mediated PI3K activation is insufficient for maintaining hESC pluripotency. Intriguingly, the same group also reported the identification of an endogenous peptide ELABELA (ELA; APELA) that acts to induce PI3K/AKT activity via an alternative, unknown receptor that is distinctly different from canonical induction via insulin (
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). Introduction of exogenous ELA alone not only sufficiently activates PI3K to the degree required for preserving pluripotency, but also primes the cells for mesendoderm differentiation, further underscoring the importance of this pathway in the regulation of ESC identity.

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Summary:
Learn about variations and the benefits and scenarios for using variations to create multilingual sites in SharePoint Server 2016, SharePoint Server 2013, or SharePoint Online.

Summary:

The variations feature in SharePoint Server and SharePoint Online makes content available to specific audiences on different sites by syncing content from a source variation site to each target variation site. When users visit the root site, they are redirected to the appropriate variation site, based on the language setting of their web browser. Content on a target variation site can be translated into other languages before it is published. Variations can be used only on sites that are created by using one of the Publishing site templates, or on sites for which the SharePoint Server Publishing Infrastructure feature was activated.

This article contains an overview of the variations feature. It describes the elements of the variations feature; provides an overview of site, list, and page creation for variation sites; lists some limitations of variations; and describes scenarios for using variations in SharePoint Server. This article does not describe the tasks that are involved in planning a solution that uses variations. For information about how to plan to use variations in your solution, see
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. This article also does not describe how to create variation labels and hierarchies. For information about how to create a variation site, see
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.

Use and benefits of variations

Many organizations have a global reach. However, even in domestic markets, organizations must reach a diverse user base that might speak many languages or that might have to have specific information that is based on regional differences. These types of organizations need websites that deliver customized content to suit different cultures, different markets, and different geographic regions. Producing and maintaining different versions of a site can be difficult and time-consuming. By using the variations feature as part of a SharePoint Server 2013 solution, site architects and site administrators can simplify the process of producing and maintaining these sites. The variations feature automates the creation, management, synchronization, and translation of sites, lists, and pages, which eliminates having to manually create a site and all associated lists and pages for each instance of a needed variation.

You can use variations to create sites, lists, and page content for specific languages. In this scenario, most of the content is authored in the language of the source variation site and synced to some or all of the target variation sites for translation into different languages. For example, the content might be authored in English and be synced to target variation sites for translation into German, French, and Spanish.

B12 levels between 200-400 have been associated with neurological damage in the scientific literature. I strongly suggest picking up a copy of the book I referenced in this article, “Could it Be B12”, reading it, and taking it in to your doctor. Many doctors are under-educated about B12 and the devastating effects of ongoing deficiency.

Just a follow up to my story. I saw a doctor last week and requested an active B12 test. I was refused outright. Thank goodness I can buy B12 and self-administer. I dread to think where I might be otherwise.

I am so thankful that I found this website and the information I read about how a serum B12 test could be 90% out because it doesn’t differentiate between active and inactive B12. If I hadn’t read that I would still be thinking I was fine as my levels are very high. However, my RBC count has dropped over the last 3 years to the lowest level of normal. I fit more than one of the risk groups, being over 60, have low stomach acid and malabsorption due to a damaged small intestine from undiagnosed gluten intolerance.

About 9 days ago I started supplementing with sublingual methylcobalamin, 1000mcg daily. I had blood tests done 2 days ago and my RBC count is on the rise! It has risen by .2 and I hope it goes up a bit more yet. I’m not sure if it will on the same dose or if I should increase it, but at least it is finally heading in the right direction.

I have been taking the LifeExtension Methylcobalamin 5mg sublingual tablets, but do not like how long it takes for them to dissolve. So, when I read about someone on here that uses the Pure Advantage B-12 spray, I was so happy! I’d much rather do a spray.

However, I just got it, and realized that it is only 500 mcg (0.5 mg). So, the question is, even though the directions say to do one spray per day … should I do 10 sprays per day to get the 5mg’s in?